Novel preparation of pregnanes

ABSTRACT

Novel process for the preparation of steroids of the pregnane series from certain estrane derivatives which pregnanes are intermediates for cortisone derivatives.

United States Patent [151 3,697,510

Bucourt et al. [451 Oct. 10, 1972 [54] NOVEL PREPARATION OF [51] Int. Cl..C07c 173/00 PREGNANES [58] Field of Search Machine Searched SteroidsI72] Inventors: Robert Bucourt; Lucien Nedelec,

both of Clichy-sous-Bois; Jean- [56] References Cmd Claude Gasc, Bondy;Andre Pierdet, UNITED STATES PATENTS NOW 16 France 3,236,868 2/1966Bowers ..260/397.45 Assigneel Rom] Udaf, Paris, France 3,280,155 10/1966Schneider et a1 ..260/397.3 [22] Filed: Oct 20, 1970 3,531,503 9/1970Cereghetu et a]. .....260/397.3

[21] Appl. No.: 82,482 Primary Examiner-Henry A. FrenchAttorney-Ha1nmond & Littell [30] Foreign Application Priority Data [57]ABSTRACT March 4, 1970 France ..7007756 Novel process for tht:preparation of Steroids of the pregnane series from certain estranederivatives which [52] US. Cl... .............260/239.55 R, 260/239.55C,

pregnanes are intermediates for cortisone derivatives.

N r e i NOVEL PREPARATION OF PREGNANES STATE OF THE ART The totalsynthesis of 19-nor steroids such as steroids of the estrane series hasbecome an industrial reality using processes described in Comptes Rendusde 1 Ac. Sciences, Vol. 250 (1960) p. 1,084 and 1293, Angewandte Chemie,1960, p. 725 and 1965, p. 185 and Chem. and Eng. News, Mar. 2, 1964, p.42.

Since then, synthetic methods have been attempted for the preparation ofcortisonic steroids. One of the first attempts was the alkylation in thel-position of intermediates in the synthesis such as described in FrenchPat. Nos. 1,255,101 and 1,550,974.

Several processes have been known for a long time for the constructionof a side chain in the l7-position but so far as is known, none havebeen commercially used because of their laborious character and themediocre yields that they give.

OBJECTS OF THE INVENTION It is an object of the invention to provide anovel process for the preparation of pregnane compounds from estranecompounds.

It is a further object of the invention to provide novel intermediatecompounds useful in the novel process.

These and other objects and advantages of the invention will becomeobvious from the following detailed description. I

THE INVENTION The novel process of the invention for the preparation ofA -pregnadiene-17a-ol-3,20-dione comprises reacting a 3-alkylenedioxy-A-"-estradiene- 17-one with an alkali metal cyanide in an acidic media toform 3-alkylenedioxy-17,8-cyano-A "-estradiene-17a-ol, reacting thelatter with a trialkyl silylating agent to form the corresponding3-alkylenedioxy-l 7,6-cyano-17a-trialkylsilanoxy-A "-estradiene,reacting the latter with a per acid to form the corresponding3-alkylenedioxy-5a, a-epoxy-l7a-trialkylsilanoxy- 1 7,8-cyano-A""-estrene and reacting the latter with a methyl magnesium halide toobtain 3-alkylenedioxy-A "-pregnene-Sa, 17a-diol-20-one. The latterproduct can be reacted in a step by treatment with an acidic agent toform A -pregnadiene-17aol-3,20-dione.

The starting materials for the process of the invention, the3-alkylenedioxy-A "-estradiene-l7-ones, are described in French Pat. No.1,336,083. In a modification of the invention, the 3-alkylenedioxyderivative can be replaced with a 3,3-dilower alkoxy derivative but thestarting material is preferably the 3.- ethylenedioxy derivative.

The reaction of the 17Bcyano compound to form the corresponding17a-triaIky1silanoxy-l7B-cyano derivative is effected by reaction with atri lower alkyl silyl halide such as trimethyl silyl chloride in asubstantially anhydrous aklaline medium such as pyridine.

The formation of the 5a, IOa-epoxy group can be formed after or beforethe formation of the 170:- triloweralkyl silanoxy group although it ispreferably formed after. The epoxy group is formed by reaction with aper carboxylic acid such as perphthalic acid, perbenzoic acid,per-p-nitrobenzoic acid, performic acid or peracetic acid in an organicsolvent such as aromatic hydrocarbons, halogenated hydrocarbons orethers.

The reaction of the l7a-triloweralkyl silanoxy-17B- cyano derivative ispreferably effected with the methyl magnesium halide in an organicsolvent. The halide is preferably the chloride, bromide or iodide andthe solvent may be tetrahydrofuran. The trilower alkylsilanoxy group iseasily hydrolyzable.

The 3-alkylenedioxy-A -pregnene-Sa, 17a-diol- 20-one produced by theprocess of the invention can be treated under acidic conditions tosimultaneously remove the alkylene ketal and dehydrate the compound inthe 4,5 position. Preferably the reaction is effected with a sulfonicresin in the acid form in an alcoholic media containing a small amountof water to form A -pregnadienel 7a-ol-3,20-dione. This latter productis a valuable intermediate for the preparation of valuablecortisone'derivatives. For example, a functional oxygen group can beadded to the ll-position and a 9a-fluoro group can be added by wellknown methods as described by Fieser and Fieser in STE- ROIDE, VelagChemie 1961, P. 754 and 786. An alcohol or esterified alcohol can beintroduced in the 21- position using the process of French Pat. No.1,273,729.

In the following examples there are'described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 Preparation OF 3-ethylenedioxy-A "-pregnene5a, l7a-diol-20-one STEP A: 24 gm of 3-ethylenedioxy-A "-estradiene-l7-one(described in French Pat. No. 1,336,083) were dissolved in 1,500 cc ofanhydrous methanol and then 53 gm of potassium cyanide were addedthereto followed by the addition of 37 cc of glacial acetic acid over 15minutes. The reaction mixture was stirred at 20 C. for 20 hours and thenanother 15 cc of acetic acid were added. The mixture was stirred for afew minutes and then was poured into water and extracted with methylenechloride. The organic extracts were washed with sodium bicarbonatesolution and with water, were dried and evaporated to dryness in vacuo.The residue was crystallized from a mixture of methylenechloride-methanol (5-1) and then from isopropyl ether, to obtain apercent yield of 3- ethylenedioxy- 1 7B-cyano-A -estradiene- 17aolmelting at 233 234 C. and having a specific rotation [a] =-l-164 (c=0.4 percent in chloroform.)

The product occurred as white crystals soluble in methylene chloride andinsoluble in methanol and isopropyl ether.

Analysis: Calculated: %C 73.87 961-! 7.97 N 4.10 Found: 73.8 7.9 3.8

STEP B: 0.345 gm of 3-ethylenedioxy-17B-cyano- 9 s rad n-17y 9 werqsisselvesl n 92.9 pyridine and then 1 cc of chlorotrimethyl silane wasadded thereto. The reaction mixture was stirred under a nitrogenatmosphere at 20-25 C. for 3 hours. The

mixture was added to a saturated aqueous sodium bicarbonate solution andthe mixture was then extracted with methylene chloride. The organicextracts were washed with water, dried and evaporated to dryness invacuo. The residue was used as is for the next step.

The residue, which was 3-ethylenedioxy-l7atrimethylsilanoxyl 7B-cyano-A"-estradiene, was obtained in about quantitative yields in the form ofan oily product soluble in chloroform and alcohol and insoluble inwater.

The IR spectrum confirmed the absence of hydroxyl and the presence ofbands corresponding to nitrile, ketal and double bond functions as wellas supplementary intense absorptions at about 9.1 g, 10.9 a, l 1.6 p.and 11.9 n.

STEP C: 0.41 gm of 3-ethylenedioxy-l7a-trimethylsilanoxy-l7B-cyano-A-estradiene were dissolved in 14 cc of chloroform and after the solutionwas cooled to 0 C. under a nitrogen atmosphere, it was poured over 6minutes into 0.215 gm of m-chloroperbenzoic acid titrating about 80percent. The reaction mixture was held at 0 C. and was stirred for 15minutes and then was poured into a saturated aqueous sodium bicarbonatesolution. The phases were separated by decantation and the organic phasewas washed with water, dried andevaporated to dryness. The residue wassubjected to chromatography over silica gel with elution with benzenecontaining percent of ethyl acetate to obtain about 60 percent yield of3- ethylenedioxy-Sa, IOa-epoxyl 7a-trimethylsilanoxyl7,8-cyano-A"-estradiene melting at l50-l55 C.

The product occurred in the form of white crystals soluble in chloroformand ethanol and insoluble in water.

STEP D: 1.3 gm of 3-ethylenedioxy-5a, IOa-epoxy-17a-trimethylsilanoxy-l7/3-cyano-A -estrene were dissolved in cc ofanhydrous tetrahydrofuran and then 35 cc of amolar solution of methylmagnesium bromide in tetrahydrofuran were added thereto. The reactionmixture was stirred under a nitrogen atmosphere for 1% hours at roomtemperature and after heating the solution to reflux, the volume of thesolution was reduced to about 15 cc. The concentrated solution wasrefluxed for 4 hours and was then allowed to stand at -25 C. overnight.The reaction mixture was diluted with tetrahydrofuran and was thenpoured into a concentrated solution of ammonium chloride. The reactionmixture was extracted with methylene chloride and the extracts werewashed with water, dried and evaporated to dryness in vacuo. The residuewas subjected to chromatography over silica gel with elution withchloroform containing 10 percent of acetone to obtain a 60 percent yieldof 3-ethylenedioxy-A "-pregnene-5a, l7a-diol-20-one melting at 160 Theproduct occurred in the form of crystals soluble in chloroform andethanol and insoluble in water.

EXAMPLE ll Preparation OF A -pregnadiene-17cz-ol-3,2O-dione 64 mg of3-ethylenedioxy-A "rpregnene-Sa, 17adiol-20-one were dissolved in 1.5 ccof 95 percent ethanol and then 0.5 gm of a cationic sulfonic exchangeresin in the acid form were added thereto. The reaction mixturewas'heated to reflux under a nitrogen atmosphere and after stirring for4 hours, the mixture was cooled and filtered. The filtrate wasevaporated to dryness and the residue was crystallized from ethyl etherto obtain about a 50 percent yield of A- -pregnadienel7aol-3,20-dionewhich was identical to a sample of the product obtained in anotherfashion.

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof and it is to beunderstood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A process for the production of a compound selected from the groupconsisting of 3-alkylenedioxy- A .-pregnene-5a, l7oz-diol-20-one and3,3-dilower alkQXy-A -pregnene-Sa, l7a-diol-20-one [A"pregnadiene-l7a-ol-3,20-dione] comprising reacting a compound selectedfrom the group consisting of 3-alkylenedioxy-A "-estradiene- 17-one and3,3- dilower alkoxy-A estradiene-l7-one with an alkali metal cyanide inan, acid media to form the corresponding l7,8-cyano-A "-estradiene- 1701-01, reacting the latter with a trilower aklyl silyl halide to formthe corresponding l7B-cyanol 7a-trialkyl silanoxy-A "-estradiene,reacting the latter with a 1 percarboxylic acid to form thecorresponding 5a, 10aepoxy-l 7a-trialkyl silanoxyl 7B-cyano-A -estrene,reacting the latter with a methyl magnesium halide to obtain thecorresponding A -pregnene-5a, l7a-diol- 20-one.

2. The process of claim 1 wherein the starting compound is3-ethylenedioxy-A -estradiene-l 7-one.

3. The process of claim 1 wherein the alkali metal cyanide is potassiumcyanide.

4. The process of claim 1 wherein the trialkylsilylating halide istrimethylsilyl chloride.

5. The process of claim 1 wherein the percarboxylic acid is selectedfrom the group consisting of perphthalic acid, perbenzoic acid,per-p-nitrobenzoic acid, performic acid and peracetic acid.

6. The process of claim 1 wherein the methyl magnesium halide isselected from the group consisting of chloride, bromide and iodide.

7. The process of claim 1 wherein the final product is reacted with anaqueous acidic agent to formA pregnenel 7a-ol-3 ,20-dione.

8. The process of claim 7 wherein the acidic agent is a sulfonic acidresin in the acid form in a lower alkanol containing a small amount ofwater.

wherein R and R are lower alkyl and when taken 7 together form a loweralkylene.

10. A compound of claim 9 wherein R and R taken together are ethylene- 1l. A compound of the formula 6 ON wherein R and R are lower alkyl andwhen taken CH3 together form a lower alkylene.

14. A compound of claim 13 wherein R and R taken OS1CH3 together areethylene.- R 1 5. A compound of the formula 1 CH3 CN wherein R and R arelower alkyl and when taken I together form a lower alkylene. l0 12. Thecompound of claim 11 wherein R and R taken together are ethylene. R0

13. A compound of the formula CH; RO

/CH: 1 5 osiqcm wherein R and R are lower alkyl and when taken CH3together form a lower alkylene. W0 16. A compound of claim 15 when R andR taken together are ethylene. R0

2. The process of claim 1 wherein the starting compound is3-ethylenedioxy- Delta 5(10),9(11)-estradiene-17-one.
 3. The process ofclaim 1 wherein the alkali metal cyanide is potassium cyanide.
 4. Theprocess of claim 1 wherein the trialkylsilylating halide istrimethylsilyl chloride.
 5. The process of claim 1 wherein thepercarboxylic acid is selected from the group consisting of perphthalicacid, perbenzoic acid, per-p-nitrobenzoic acid, performic acid andperacetic acid.
 6. The process of claim 1 wherein the methyl magnesiumhalide is selected from the group consisting of chloride, bromide andiodide.
 7. The process of claim 1 wherein the final product is reactedwith an aqueous acidic agent to form Delta 4,9(11)-pregnene-17 Alpha-ol-3,20-dione.
 8. The process of claim 7 wherein the acidic agent is asulfonic acid resin in the acid form in a lower alkanol containing asmall amount of water.
 9. A compound of the formula
 10. A compound ofclaim 9 wherein R and R'' taken together are ethylene.
 11. A compound ofthe formula
 12. The compound of claim 11 wherein R and R'' takentogether are ethylene.
 13. A compound of the formula
 14. A compound ofclaim 13 wherein R and R'' taken together are ethylene.
 15. A compoundof the formula
 16. A compound of claim 15 when R and R'' taken togetherare ethylene.